Stress-related diseases are accompanied by glucocorticoid and cardiovascular dyshomeostasis. In particular, glucocorticoid hypersecretion in depression is linked with both ongoing mood symptoms and with long-term physiological dysfunctions, including osteoporosis and visceral obesity. Decreased heart rate variability is associated with negative emotions in depressed patients, and contributes to the high incidence of cardiovascular pathology and mortality associated with the disorder. Thus, physiological consequences of depression contribute to both psychiatric symptoms and co-morbid disease processes. Neural and systemic effects of depression are linked to inappropriate processing of stressful information in the brain. The current proposal uses rodent chronic stress models to address mechanisms that control physiological adaptation and dysfunction following long-term stress. Our proposal tests the novel hypothesis that distinct brainstem neurons act as critical integrators of both stress habituation and sensitization, and are thereby responsible for adaptive as well as maladaptive hormonal and autonomic responses. Aim 1 will determine whether noradrenergic neurons of the nucleus of the solitary tract (NTS) are responsible for driving HPA axis hyperactivity and autonomic dysfunction following chronic stress. Aim 2 tests the hypothesis that neuroendocrine and autonomic stress pathologies are mediated through inappropriate drive of NTS noradrenergic neurons by forebrain stress-recruited pathways. Aim 3 uses a NTS gene knockdown approach (lentiviral vectors) to examine the role of NTS glucagon-like peptide 1(GLP-1) neurons in long-term stress adaptation. Aim 4 is designed to elucidate the role of NTS glucocorticoid receptor-mediated feedback in the control of stress adaptation and pathology. Understanding the role of the NTS in stress adaptation will add new insight into potential circuit pathology in affective disease, and provide novel molecular targets (GLP-1, brainstem glucocorticoid receptors) for development of therapeutic intervention strategies.